In humans, the sense of smell is critical for protection against external hazards including or gas, fire and in the consumption of food. Perturbations of the olfactory system cause loss of appetite and poor nutrition, particularly with older patients. For example, the average human loses a significant proportion of their olfaction as they age, and olfactory dysfunction is associated with several aging-related diseases including Alzheimer's and Parkinson's disease. Olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) are constantly insulted by exogenous stress, which includes exposure to volatile toxic chemicals and bacterial infections. The olfactory system has the exquisite capacity to discriminate between an immense variety of odorants. Furthermore, OSNs in the MOE exhibit a number of short-term and long-term adaptive changes in response to odorant exposure. This grant focuses on mechanisms that mediate the detection of odorants and contribute to transcription-dependent, long-term adaptive responses in the MOE. It is our hypothesis that cAMP signals generated through odorant activation of the type 3 adenylyl cyclase (AC3) play a key role in olfaction. We propose that termination of AC3 activity by calmodulin-dependent protein kinase II (CaMKII) contributes to olfactory-based behavioral responses including chemotaxis to odorants. We also propose that cAMP and Ca2+-mediated activation of the CREB/CRE transcriptional pathway by odorants mediates long-term adaptive responses in the MOE including odorant-induced activity-dependent survival of OSNs and proliferation of immediate neuronal precursors. This general hypothesis will be examined using inducible transgenic mouse strains lacking AC3 and calmodulin-dependent proteins kinase II activities as well as adenovirus-mediated expression of dominant-negative and constitutive-active MEK and CREB in the MOE. These studies should provide fundamental information concerning neuronal signaling mechanisms in the OSNs, and may ultimately provide new insights concerning clinical and pharmacological strategies to prevent anosmia associated with aging, bacterial infections, and neurodegenerative diseases.